Mechanisms of ketosis and near-normoglycemia remission in obese African Americans with ketosis-prone diabetes

患有酮症倾向糖尿病的肥胖非裔美国人的酮症和接近正常血糖缓解的机制

• 批准号: 10676968
• 负责人: Priyathama Vellanki
• 金额: $ 11.74万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676968
• 关键词: Affect; African American; African American population; Amino Acids; Beta Cell; Biological Assay; Blood Glucose; Branched-Chain Amino Acids; Catabolism; Cell physiology; Cell secretion; Characteristics; Clinical; Data; Defect; Diabetes Mellitus; Diabetic Ketoacidosis; Disease remission; Evidence based intervention; Exhibits; Fasting; Fatty acid glycerol esters; Glycosylated hemoglobin A; Hepatic; Hyperglycemia; Image; Immunologics; Impairment; In Vitro; Insulin; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Ketones; Ketoses; Ketosis; Knowledge; Lead; Leucine; Lipids; Lipolysis; Liver; Magnetic Resonance Imaging; Maintenance; Metabolic; Methodology; Modality; Newly Diagnosed; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Organ; Pancreas; Participant; Pathway interactions; Patients; Persons; Phenotype; Plasma; Production; Recording of previous events; Recovery; Relapse; Resolution; Sampling; Time; acylcarnitine; beta-Hydroxybutyrate; comparison control; experience; fasting glucose; fatty acid metabolism; follow-up; glucose production; improved; in vivo; insight; insulin secretion; insulin sensitivity; intrahepatic; ketogenesis; ketogentic; metabolomics; novel; oxidation; prevent

Project Summary/Abstract It is estimated that ketosis-prone diabetes mellitus (KPDM) affects 20-50% of African American patients with newly diagnosed diabetes who present with diabetic ketoacidosis (DKA). At presentation of DKA, these patients have a severe decompensation in insulin secretion accompanied by severe insulin resistance. Unlike patients with type 1 diabetes, following intensive insulin treatment, many of these patients exhibit improvements in insulin secretion and insulin sensitivity and are able to discontinue insulin therapy (near- normoglycemia remission, HbA1c < 7%, fasting glucose < 130 mg/dl while off insulin for at least one week). The period of near-normoglycemia remission is variable and many patients eventually experience a hyperglycemic relapse or even DKA while some stay in remission due to sustained insulin secretion. Despite the phenotype being recognized for many years, the underlying mechanisms leading to ketosis and maintenance of beta-cell function are unknown. Further, increased intra-organ (pancreas and liver) fat can also play a role in remission. High resolution metabolomics and magnetic resonance imaging offer a comprehensive way to assess multiple pathways and imaging characteristics. This proposal will leverage already collected samples and participants from the PI’s K23 proposal to examine pathways leading to ketosis and sustained remission. Aim 1 will compare metabolomic signatures between people with DKA and hyperglycemia without ketosis. Aim 2 will compare metabolomic signatures at time of insulin discontinuation and their relationship with sustained beta-cell function. Aim 3 will explore whether differences in pancreatic and hepatic fat associate with sustained remission and beta-cell function. The Aims, together with new collaborators with complementary expertise will generate data to explore novel hypotheses for new independent proposals by the PI.

项目摘要/摘要 据估计，容易发挥酮症的糖尿病（KPDM）会影响20-50％的非裔美国人患者 新诊断的糖尿病患有糖尿病性酮症酸中毒（DKA）。在介绍DKA时，这些 患者在严重的胰岛素抵抗进行的胰岛素分泌方面具有严重的代偿性。与众不同 1型糖尿病患者，在强化胰岛素治疗后，其中许多患者表现出 胰岛素分泌和胰岛素敏感性的改善，并能够停止胰岛素治疗（接近 - 正常血糖缓解，HBA1C <7％，禁食葡萄糖<130 mg/dL，而胰岛素持续至少一周）。 接近肺炎血症缓解的期间是可变的，许多患者最终经历了 由于持续的胰岛素分泌，有些人保持缓解，高血糖的缓解甚至DKA。尽管 表型被识别多年，导致酮症和 β细胞功能的维护尚不清楚。此外，增加的器官（胰腺和肝脏）脂肪也可以 在缓解中发挥作用。高分辨率代谢组学和磁共振成像提供了全面的 评估多个途径和成像特征的方法。该建议将利用已经收集的 PI K23提案的样本和参与者检查导致酮症并持续的途径 缓解。 AIM 1将比较患有DKA和高血糖的人之间的代谢组学特征 酮症。 AIM 2将比较胰岛素中断时的代谢组学特征及其与之的关系 持续的β细胞功能。 AIM 3将探索胰腺和肝脂肪的差异是否与 持续缓解和β细胞功能。目的与新的合作者一起完成 专业知识将生成数据，以探索PI新的独立建议的新假设。